1. Field of the Invention
This invention relates to compositions such as those used for coating implantable medical devices such as stents.
2. Description of Related Art
Percutaneous transluminal coronary angioplasty (PTCA) is a procedure for treating heart disease. A catheter assembly having a balloon portion is introduced percutaneously into the cardiovascular system of a patient via the brachial or femoral artery. The catheter assembly is advanced through the coronary vasculature until the balloon portion is positioned across the occlusive lesion. Once in position across the lesion, the balloon is inflated to a predetermined size to radially compress against the atherosclerotic plaque of the lesion to remodel the vessel wall. The balloon is then deflated to a smaller profile to allow the catheter to be withdrawn from the patient's vasculature.
A problem associated with the above procedure includes formation of intimal flaps or torn arterial linings which can collapse and occlude the conduit after the balloon is deflated. Moreover, thrombosis may develop shortly after the procedure and restenosis of the artery may develop over several months after the procedure, which may require another angioplasty procedure or a surgical by-pass operation. To reduce the partial or total occlusion of the artery by the collapse of arterial lining and to reduce the chance of the development of thrombosis and restenosis, a stent is implanted in the lumen to maintain the vascular patency.
Stents are used not only as a mechanical intervention but also as a vehicle for providing biological therapy. As a mechanical intervention, stents act as scaffoldings, functioning to physically hold open and, if desired, to expand the wall of the passageway. Typically, stents are capable of being compressed, so that they can be inserted through small lumens via catheters, and then expanded to a larger diameter once they are at the desired location. Biological therapy for reducing or eliminating thrombosis or restenosis can be achieved by medicating the stents. Medicated stents provide for the local administration of a therapeutic substance at the diseased site. In order to provide an efficacious concentration to the treated site, systemic administration of such medication often produces adverse or toxic side effects for the patient. Local delivery is a preferred method of treatment in that smaller total levels of medication are administered in comparison to systemic dosages, but are concentrated at a specific site. Local delivery thus produces fewer side effects and achieves more favorable results.
Local delivery can be accomplished by coating the stent with a polymeric carrier containing a biologically active agent. A polymer dissolved in an organic solvent and the agent added thereto are applied to the stent and the organic solvent is allowed to evaporate, leaving a polymeric coating impregnated with the agent.
Biologically active agents including polysaccharides, e.g., heparin, and polycationic peptides, e.g., poly-L-arginine have proven to provide beneficial effects in the treatment of thrombosis and restenosis, more particularly when used in conjunction with a stent. However, incorporation of these compounds into a polymeric carrier has proven to be challenging due to such compounds' limited solubility. To pose the problem more concretely by way of example, heparin is soluble in water but not in organic solvents, while conventional polymers used for the sustained release of heparin are soluble in organic solvents but not water. To avoid the problem of solubility incompatibility, efforts have been made to fabricate heparin-polymer coatings from heparin-polymer suspensions. For example, U.S. Pat. Nos. 5,837,313 and 5,879,697, disclose micronizing heparin followed by physically blending with a polymer and solvent to form the suspension. The suspension methods have drawbacks and disadvantages. The manufacturing process, for example, requires spraying equipment capable of handling particles. In addition, heparin-polymer suspensions lack sufficient stability in the absence of suspension agents and require constant agitation during the coating process.
Alternatively, a complex of heparin with a cationic surfactant can be formed for converting the heparin into an organically soluble compound. Examples of suitable surfactant counter ions include benzalkonium and tridodecylmethyl ammonium. However, a surfactant-bound heparin has lower antithrombotic activity because the surfactant alters heparin's charge balance and binding coefficient with coagulation cofactors.
In view of the foregoing, there is a need to prepare a true solution of polysaccharides and cationic peptides with organic solvent compositions commonly used to form polymeric coatings on implantable medical devices.